Atopic dermatitis (AD) is a chronically recurrent cutaneous inflammatory disease which may affect up to 10% of the population. The condition is part of the atopic triad which also includes asthma and allergic rhinitis. These diseases have strong hereditary patterns but the genetics is unclear. AD is characterized by a variety of immunologic and pharmacologic abnormalities, and evidence from transplant studies indicates that the basic abnormality is expressed in bone marrow cells. Defects such as increased basophil histamine release and high spontaneous IgE production by B lymphocytes imply defective cellular regulation. Abnormalities of cyclic nucleotide metabolism have been demonstrated in AD and elevated cAMP-phosphodiesterase (PDE) activity with resultant low intracellular cAMP levels may have a net permissive effect on immune and inflammatory responses. Chromatofocusing studies of abnormal PDE have demonstrated two distinctly abnormal cytosolic fractions of PDE activity in monocytes and lymphocytes. The recent development of monoclonal antibodies to PDE's now provides us with the means to characterize and isolate abnormal enzyme forms. We will expand upon preliminary evidence for phosphorylation as a mechanism of PDE activation and study proteolytic effects on enzyme structure and activity. We will use immunodetection assays for predictive screening of atopic individuals and for identifying specific leukocyte subsets. Another major effort will be directed at induction of leukocyte activation markers and abnormal PDE mononuclear leukocytes by immune effector factors produced by AD leukocyte cultures and potentially by specific cytokines. Finally we intend to study cord blood leukocytes for elaboration of activation factors and for abnormal PDE activity as predictors of atopy and bronchopulmonary dysplasia. These studies are directed at determining primary events leading to atopy, to provide biochemical markers of disease and to clarify abnormal biochemical and immunological mechanisms associated with increased PDE in atopic dermatitis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI018615-09
Application #
3128047
Study Section
General Medicine A Subcommittee 2 (GMA)
Project Start
1982-05-01
Project End
1991-08-31
Budget Start
1990-09-01
Budget End
1991-08-31
Support Year
9
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Oregon Health and Science University
Department
Type
Schools of Medicine
DUNS #
009584210
City
Portland
State
OR
Country
United States
Zip Code
97239
Chan, S C; Brown, M A; Willcox, T M et al. (1996) Abnormal IL-4 gene expression by atopic dermatitis T lymphocytes is reflected in altered nuclear protein interactions with IL-4 transcriptional regulatory element. J Invest Dermatol 106:1131-6
Hanifin, J M; Chan, S C; Cheng, J B et al. (1996) Type 4 phosphodiesterase inhibitors have clinical and in vitro anti-inflammatory effects in atopic dermatitis. J Invest Dermatol 107:51-6
Toshitani, A; Ansel, J C; Chan, S C et al. (1993) Increased interleukin 6 production by T cells derived from patients with atopic dermatitis. J Invest Dermatol 100:299-304
Chan, S C; Kim, J W; Henderson Jr, W R et al. (1993) Altered prostaglandin E2 regulation of cytokine production in atopic dermatitis. J Immunol 151:3345-52
Chan, S C; Reifsnyder, D; Beavo, J A et al. (1993) Immunochemical characterization of the distinct monocyte cyclic AMP-phosphodiesterase from patients with atopic dermatitis. J Allergy Clin Immunol 91:1179-88
Li, S H; Chan, S C; Kramer, S M et al. (1993) Modulation of leukocyte cyclic AMP phosphodiesterase activity by recombinant interferon-gamma: evidence for a differential effect on atopic monocytes. J Interferon Res 13:197-202
Chan, S C; Li, S H; Hanifin, J M (1993) Increased interleukin-4 production by atopic mononuclear leukocytes correlates with increased cyclic adenosine monophosphate-phosphodiesterase activity and is reversible by phosphodiesterase inhibition. J Invest Dermatol 100:681-4
Chan, S C; Hanifin, J M (1993) Differential inhibitor effects on cyclic adenosine monophosphate-phosphodiesterase isoforms in atopic and normal leukocytes. J Lab Clin Med 121:44-51
Li, S H; Chan, S C; Toshitani, A et al. (1992) Synergistic effects of interleukin 4 and interferon-gamma on monocyte phosphodiesterase activity. J Invest Dermatol 99:65-70
Hanifin, J M; Lloyd, R; Okubo, K et al. (1992) Relationship between increased cyclic AMP-phosphodiesterase activity and abnormal adenylyl cyclase regulation in leukocytes from patients with atopic dermatitis. J Invest Dermatol 98:100S-105S

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